CA2223442A1 - Biocompatible optically transparent polymeric material based upon collagen and method of making - Google Patents

Abstract

The present invention is a biocompatible polymer containing the copolymerization product of a mixture of hydrophobic and hydrophilic acrylic and/or allelic monomers, graft-polymerized with telo-collagen. The present material is useful in the production of deformable lenses, for example, intraocular lenses, refractive intraocular contact lenses, and standard contact lenses useful, for example, for correcting aphakia, myopia and hypermetropia.

Description

W O 96/40818 PCT~S96/10013 Tiale oltlle lllvelllion I~iocompatible Optically Transparent rolymeric Material I~ased Upon Collagen and Method of ~zlkin~

10 .RP1~te(1 A~)plication This appli~ on is a con~inl-~fioll-in-part application of U.S. patent applic~ion Serial No.
08/279,303, filed July 22, 1994, which application is incorporated by reference in its entirety.

15 P'ield of lhe Invention This invention relates to a biocompatible polymer cont~ining the copoly.~ ion product of a mi~cture of hydrophobic and hydrophilic acrylic and/or allelic monomers, and telo-coll~en pre1imin~rily purified from glucoproteins and proteogluc~nps. The rn~ri~l is 20 useful for lhe pro-iuction of soft intraocular lenses, refractive intraocular contact lenses, and standard contact lenses useful for example, in correc~ing aphekia, myopia and hy~GI---tl-ol~ia.

I~ackground of t~le Invention 25Ol.linal~ polymers, based upon pure non-polyenic acryla~es or allelic monomers, do not have on their surfaces water-solvent ionic layers on their surfaces whicll are buffered against the WO 96/40818 PCT~US96/10013 --2 --sorption of proteins. Providing waLer-solvent iollic layers on lhe surface of the polymer is desirable because SuCIl layers will grea~ly improve the bio-compalibility of the lens with cell membranes of the recipient's eye.

Polyenic water-solvent ionic monomers may be used in or(Jer to produce a water-solvent layer. However, this decreases tl)e rÇ~i~t~nCe of such copolyrners against swelling. For example, the system of polyenic copolymers, I)ased upon acrylarnid or acrylic acid wilh HEMA
has a t~ondency towards excessive swelling beyond all bounds. This happens because pure homopolymers, polyacrylamide or polyacrylic acid, contained in Ihis system, dissolve in water.
Therefore, it is an advantage to produce a polymer which would be able to form such a vital water-solvent layer, and would not affect the polymer resislance against swelling.

References concerning graft-copolymers of collagen include U.S. Patent No. 4,388,428 aune 14, 1983) and U.S. Palent No. 4,452,925 aune 5, 19g4). In these p~t~.n~.~, a system of water-soluble monomers and A telo-collagen is used. However, this system is not hydrolytically stable and is not sufficiently optically transparent. In U.S. Patent No. 4,452,925, nothing is mentioned of special optical conditions needed for transparent polymer production. The water-solvent A telo-collagen di~closed in this patent does not have the capacity to form a gel in the organic monomer solution, and lherefore the collagen precipitales or coagulates.

51~rnn~ y of ~e Invention An object of the present invenlion is to provide a biocompatible optically transparent polymeric material based on telo-collagen.

A further object of the present invenLion is to provide a biocompatible polymer cont~ining the copolymerization product of a mixture of llydropllol)ic and hydrophilic acrylic and/or allelic type-monomers and telo-collagen.

~n obiect of the present invention is to provide a metllod of making a biocompatible, optically transparent, polymeric material based on collagen A further object of tlle present invention is to provide a method of making a biocompatible polymer containing t1le copolymerization product of a mixture of hydrophobic and 15 llydrophilic acrylic and/or allelic type-monomers and telo-collagen.

The present invention is directed to metllods of making a biocompatible polymeric material based on collagen for use in the production of derormable lenses.

The present invention is also directe(l lo an derormable lens comprised of the present optically transparent, biocompatible, polymeric material.

The present invention is further directed to methods for making deformable lenses.
s The present invenlion is also directed to methorls for correcting aphekia (absence of the lens of the eye), myopia or hypermetropia in a patient by surgically implanling in the eye of the patient, tlle present deformable lens.

The biocompatible polymeric material according to the present invention is made as a copolymerization product of a mixture of hydrophol)ic and hydrophilic acrylic and/or allelic monomers graft polymerized with telo-collagen. For example, one or more hydrophobic acrylic and/or allelic monomers are mixed wilh one or more hydrophilic acrylic and/or allelic monomers, and the resul~nt solution is then mixed with telo-collagen dissolved in one or more 15 hydrophilic acrylic and/or allelic monomers. Tlle resul~ing malerial is then irradiated to form the present biocompatible optically transparent polymeric m~eri~l The telo-collagen used in the present invention is ~centi~lly type IV collagen obtained from pig's eye sclera or cornea. The collagen is a naturally stable polyenic, which comprises 20 hydrophobic, hydroxylic and polarized amino-acids (l~tcum--ra, T., }~ ion~hip Between Amino-Acid Composition and Differentiation of Collagen, Lut. J. Biochem. 3(15):265-274 _ 5 _ (1972), and Traub W., and Piez K.A., The l'hPn-icfry and Slructure of Collagen, Advances in Pro~ein Cffern 25:243-352, (1971). It is nol a~ visable lo use a modified collagen in the system according to the present invention since this collagen biodegrades wilh time (U.S. Palent No.

4,978,352, December 18, 1990).

The resulling biocompalible polymeric malerial is an elaslic biopolymer, basf~ upon the mixture of llle hydrophobic and hydrophilic monomers and telo-collagen. The product of the hydropllobic and hydrophilic monomer copolymerizalion exhibils an elevated hydrolytic stability and a mucll higher index of refraction, if compared wilh a polymer which is based upon 10 hydrophilic monomers alone.

The high molecular mass of lelo-collagen molecules (320,000D), their size (up to lOOOA), the disorientalion of molecules in space, the refraclion index 1.47 (Hogan J. J. et. al., ~Iistology of Huma~l Eyes, A~ Atla~ an~l Text~ook, rhiladelphia, London, Toronto, (1971)), and 15 other characleristics of collagen make it impossible to produce oplically Iransparent hydrogel impl~nfc made of collagen alone. The refraclion index of the hydrogel base substance, the aqueous number is equal to 1.336, whicll is subsf~n~iz.lly ~fifferent from the refractive index of collagen 1.47, resulting in opacificalion of Ihe gel, if a suspension of collagen in aqueous monomer is made.

In order to produce an optically homogeneous gel in the mixlure of organic monomers it is nPcecs~y to utilize telo-collagen containing lelo-peplide. Telo-peptide is tlle basic element of inl~ tion among collagen molecules. Tllis produces a stable gel in the mixture of hydrophobic and hydrophilic monomerS, and this gel neilher precipitates nor coagulates.

For the purpose of increasing the oplical transparency and homogeneity in this system, the refraction index of polymer and of lelo-collagen should be appro~im~ly equal, so that the intensity of light diffusion is close lo zero, in accordance wilh Reley's equation (U.G. I;rolof, Course of Colidle C~lemistry, Moskva Chemia, 1989):

~ fN,2 - N 2 \ c.v2 WHEREAS, I = Io 24~r3 ~ (1 + COS2 w) N,2 + 2No2 ~ Pl /

15 L-- is intensity of inrident light;

-- is the intensity of diffused ligl-t as a Ul1it of radiation volume;

20 P, = flict~nce to detector;

w = light diffusion angle;

W O 96/~0818 PCT~US96/10013 C = concentration of particles per volume unit;

= lengtll of incident lighl wave;

5 N = refraction index of particles;

N. = refraction index of basal substance; and V = volume of particles.

If N = No~ then Ir = O. Thus Ille inlensily of light diffusion is zero.

A preferred llydropllilic acrylic monomer for use in the present invention is 2-hydroxyelllyl me~h~crylate (HEMA) and a preferred hydrophobic monomer for use in the 15 present invenlion is 4-metharyloxy-2-hydroxybenzophenone. Tlle lelo-colla~en is preferably produced from pig s eye sclera or cornea.

WO 96/40818 PCT~US96/10013 Detailed ~es~ liorl of ~e Preferre~ Emboditnents I. Defnitions:

Tl1e below definitions serve to provide a clear and concictent understanding of the specification and claims, including the scope to be given such terms.

Telo-collagen. By tlleterm "telo-collagen" is intended for the purposes of this invenlion a naturally stable polyenic, that contains hydropllobic, llydroxylic and polarized amino-acids (M~ mllra, T., 12e~ nnch ip Between Amino-Acicl Composition and Differçn~i~tion of Collagen Lut. J. Bioc~lem 3(15J:265-274 (1972).

The present telo-collagen is essenlially type IV telo-collagen preferably made from pig's eye sclera or cornea, and has a viscosily of greater tllan or equal to lOOOcPs. The present telo-collagen retains the telo-peptides and has a refractive index of about 1.44 to 1.48.

I~ioeo~ tible polymeric matenal. By the terminology "biocompalible polymeric materialH is in~er~ l a material whicll is made by coml)illing or mixing one or more hydrophobic monomers (acrylic and/or allelic monomers), and one or more hyclrophilic monomers (acrylic WO 96/40818 PCT~US96/10013 and/or allelic monomers), and graft-copolymerizin~ tlle resultant mixture with a telo-collagen/hydropllilic monomer/acid SO~ iOII.

Monomer. By the term "monomer" denotes llle molecular unit that by repetition, S con~ti~ s a large struclure or polymer. I~or example etllylene CH2=CH2 is the monomer of polyelhylene, H(CH2)NH.

Allyl. By lhe lerm "allyl" is i~llellded 2-propenyl, lhe monovalent radical, CH2 =CHCH2-.

Organic Acid. By the lenn "organic acid" is inlended an acid made up of molecules con~qinin~ organic radicals. Such acids include for example, formic acid I~H-COOH), acetic acid (CH3COOH) and citric acid (C6H,~O7), all of which contain the ionizable -COOH group.

Acrylic. By the term "acrylic" is intended synlhelic plaslic resins derived from acrylic acids.

Optically 'rtansparent. By the terminology "optically transparent" is inten(le~l the plUpel ly of a polymeric malerial lo allow the passage of light at or above the threshold of visual 20 senQq~ion (i.e., the minimum amount of ligllt intensity invoking a visual sensation). Preferably, WO 96/40818 PCT~US96/10013 lhe present biocompalible polymeric malerial including COLLAMER has a refractive inde~c in the range of 1.44 to 1.48, more preferably 1.45 lo 1.47, and most preferably 1.45 to 1.46. The best mode of the present invention is tlle biocompatible polymeric material COLLAMER.

Polyrnerizatfon. By the term "polymerization" is in~Pnded a process in which monomers combine to form polymers. Such polymerizalion can include "addition pol~ne.i~tionH where monomers combine and no olher producLs are produced, and "cnnden~tion polymerization"
where a by-product (e.g. water) is also formed. Known suitable polymerization processes can be readily selected and employed for Ihe production of the present biocompatible polymeric mateAal by those of ordinary skill in the art to which the present invention pertains.

Polyene. By the term "polyene" is inLended a chemic~l compound having a series of conjugated (alternating) double bonds, e.g., Ihe carotenoids.

Refractive Index. By the terminology "refractive index" is intended a measurement of the degree of refraction in translucentllransparent subslances, e~peci~lly the ocular media. The "refractive index" is measured as the relative velocity of light in anotller medium (such as the , present polymeric malerial) as compared lo Llle velocity of light in air. For example in the case ~ of air to crown glass Ihe refractive index(n) is 1.52 in Ille case of air to water n= 1.33.

Tensile Strengt~l. By the terminology "lensile strenglh" is intçncied the m~xim~l stress 5 or load that a malerial is capable of s~ inillg expressed in kPa. The present biocompatible polymeric material including COLLAMER has a lensile strength in the range of about 391-1778 kPa preferably 591-1578 kl'a more preferably 791-1378 kPa and most preferably in the range of from 991 kPa to 1178 kPa. The presenl material "COLLAMER" has a tensile strength of preferably 1085 i 493 kPa. The tensile strenglll of a polymeric m~çri~l can be readily 10 determined using known melhods by those of ordinary skill in the art.

Hypennetropia. By the term "hypermetropia" (h.) is intended farsiglltef~nP-s~/longsigllt~lnç~s i.e. long or far sight which is an oplical condilion in which only convergent rays can be brought to focus on the retina. Such conditions include: (1) absolute h.--15 that cannot be overcome by an effort of accommodalion; (2) axial h.--h. that is due to shortening of tlle anteroposterior f1i~mçtçr of the globe of the eye; (3) curvature h.--h. which is due to the dec~ased refraction of the anterior di~me~r of Lhe globe of Ille eye; (4) manifest.--h. that can be comp.on~ by accommodation; (5) facultative h.-- manifest h.; (6) latent h.-- the difference W O 96/40818 PCT~US96/10013 between total and manifest h.; and (7) total In-- Ihat wllicll can be determined after complete paralysis of accommodation by means of a cycloplegic; (8) index h.--ll. arising from decreased refractivity of tlle lens.

Myopia. By ll~e term myopia (m) is intended sllortsighl~ ineSs; near~ighlPlness; near or short sight; that optical condition in wllicll only rays a finite ~ nce from lhe eye focus on tlle retina. Such conditions include: (1) axial m.--m. due to elongation of the globe of the eye;

(2) curvalure.-- m. due to refractive errors rçs llting irom excessive corneal curvature; (3) degenerative.--patllologic m.; (4) index m.--m. arising from increased refractivity of the lens as in nuclear sclerosis; (5) malignant.--palllologic m.; (6) night.--m. occurring in a normally emmetropic eye because long light rays focus in front of tlle retina; (7) pathologic.--degenerative or m~ n~nt progressive. marked by fundus changes posterior staphyloma and subnormal corrected acuity; (8) prematurity m. .--m. observed in infants of low birtll weight or in association with retrolental fibroplasia; (9) senile lenticular.--second sight; (10) simple m.--m.
arising from failure of correla~ion of the refraclive power of the anterior segment and the length of the eyeball; (11) space.--a type of m. arising when no contour is imaged on the retina; and (12) tr~nci~n~--m. observed in accommodative spasm seconr~ry to iridocyclitis or ocular co~ t-- ~ior ~ IydropJIilic allelic motlo-ner. By lhe lerm "hydropllilic allelic monomer" is int~.ndelJ
for the purposes of lhe present inventioll any monomer conlaining an allyl group wllich monomer is soluble in water.

~ ydrop~lilic acrylic rnonomer. By Ihe terminology "hydrophilic acrylic monomer" is in~n(lecl any monomer cQnt~ining an acrylic group whicll monomer is solul)le in water. ~or PY~mrle, HEMA is a hydropllilic acrylic monomer because il is soluble in water even though it contains bolh hydrophilic groups and l-ydropllobic groups.

~Iydrop~lobic allelic monorner. By ll-e lenn "hydropllobic allelic monomer" is inlended for tlle purposes of llle present invenlion, any monomer contai~iing an allyl group, whicl monomer is not soluble in water.

~Iydrop~obic ac~ylic monorner. By Ille term "hydropllobic acrylic monomer" is intendef~
for the purposes of the present invention, any monomer containing an acrylic group, which monomer is not soluble in water.

Defonnable lens. By the term "deformable lens" is intended any type of deformable lens, for eY~mplt-, for correcting hypermetropia or myopia, where tlle lens comprises the present material. Such lenses include those disclosed in U.S. Patent Applicalion Serial Nos. 08/318,991 and 08/225,060. All of the foregoing are hereby incorporaled by reference llerein. Such lenses include: intraocular lenses for implantation inlo a palienl's eye, for example, into Ille anterior cllamber, in the bag or in the sulcas; refraclive inlraocular lenses for impl~n~ti- n into a patient's eye, for example, into the anterior chamber or in tlle sulcas; and standard sort contact lenses.
s ~ mplan~. By the term "implant" is intended tlle surgical melllod of introducing the present lens into the eye of a palient, for example, into the anterior chamber, in the bag or in the sulcas, by Ihe melhods described in U.S. Palent Applicalion Serial Nos. 08/195,717, 08/318,991, and 08/220,999 using for example, surgical devices disclosed in U.S. Palent Application Serial Nos. 08/197,604, 08/196,855, 08/345,360, and 08/221,013. All of the foregoing are hereby incorporaled by reference.

The present hydropllilic monomers and hydrophobic monomers must be selec~d such that the hydrophobic monomer(s) is soluble in tlle llydrophilic monomer(s). The hydrophilic 15 monomer acts as a solvent for the hydropllol)ic monomer. Suitable monomers can be readily sele~t-oJl by those of ordinary skill in the art lo which the presenl invention pertains.

Examples of suilable ~Iydrop~lobic monomers, include:

1) 4-methacryloxy-2-hydroxybenzophenone (acrylic);

W O 96/40818 PCT~US96/10013 2) ethyl-3 benzoil acrylate (acrylic);

3) 3-allyl-4-hydroxyacetophenone (allelic);

4) 2-(2'-hydroxy-3'-allyl-5'-1llelllylpllenyl)-2H-benzotriazole (allelic);

5) N-propyl me.lf-~rrylale (acrylic);

6) allyl benzene (allelic);

7) allyl butyrate (allelic);

8) allylanisole (allelic);

9) N-propyl melhacrylale (acrylic);

10) ethyl-melh~crylate (acrylic);

11) metllyl metll~crylate (acrylic);

12) n-heptyl melhacrylate (acrylic).

Various examples of suitable ~yclt-op~lillc monomers, include:

1) 2-hydroxyethyl melhacrylale (HEMA) (acrylic);
2) hydroxypropyl methacrylate (acrylic);
3) 2-hydroxyetllyl me.lh:lr.rylate (acrylic);
4) hydroxypropyl methacrylate (acrylic);
5) allyl alcohol (allelic);
6) poly(ethylene glycol)n monomelhacrylate (acrylic);

W O 96/40818 PCT~US96/10013 7) 4-hydroxybutyl me~ crylate {acrylic);
8) allyl glucol carbonate (allelic).

II. A~etJIod of Making t~e r'resent Polymeric ~ate~ial l~ased on Collagen s The following is a descriplion of a pre~erred metllod of making lhe biocQmp~ible polymeric material according lo lhe present invenlion.

Step 1:

The hydrophilic monomer is mixed wilh an acid, in particular formic acid. The weigllt ratio of hydrophilic monomer to acid is preferably in the range of about 5:1 to about 50:1, preferably 14:1 to 20:1, and most preferably, 14:1. This solulion is preferably filtered through a 0.2 microfiller.

Step 2:

In an independent step, an acidic telo-collagen solulion is prepared by mixing telo-collagen wilh organic acid (preferably formic acid). The solution is preferably 2 % by 20 weight telo-collagen in 1 M formic acid.

Step 3:

The solutions resul~ g from steps l and 2 are lhen mixed togelller. The res~ nt solution is preferably mixed from about 10 minutes to 60 minules, ntost preferably 20 min~ s S at a lemperalure of 15-30~C. Tlle ratio of lelo-collagell to hydropllilic monomer is about 1:2 to about 1:7, preferably 1:3 to 1:6, and most preferably 1:4.

Step 4:

In an independent slep, lhe hydropllobic monomer and hydropllilic monomer are mixed logelher in a weigllt ratio of aboul lO: l lo l: l, preferably 8: l to 3:1, and most preferably 5:1. The monomers are mixed wilh stirring for about 30 lo 90 minutes, preÇerably 60 minu~es at 70 to 95~C, preferably 80-95~C, and most preferably 80-92~C. The res~ in~ solution is preferably filtered through a 0.2 micron filller.

Step 5:

The solulions from sleps 3 and 4 are mixed logelher in a weighe ralio in the range of about 1:1 to 50: 1, preferably 2: I to 5: l, and most preferably 3: 1. The solution is prererably W O 96/40818 PCT~US96/10013 mixed 20 minutes with no heating at a temperalure of 25-40~C. Mixing is preferably performed with a homogenizer.

Step 6:

The resulting material from Step 5 is thell preferably degassed (i.e., using centrifugalion or other means well-known to tllose of ordinary skill in the art to whicll the present invention applies).

0 Slep 7:

The resulting material from Step 6 is irradiated to form a final product that can be dried, and stored, (i.e., stored in a desiccator due to its hydroscopic nature). The material from Step 6 can also be stored in a refrigerator, for example at 5~C to 10~C, prior to irradiation.
A polymeric material according to the present invention is obtained from an interaction l~etw~ll a solution of telo-collagen complex, and the hydropllilic and the hydrophobic monomers under radiation of lMrad/hr for a to~al dose of from 0.20 to 0.80Mrad, preferably 0.30 to 0.60Mrad, and most prererably rrom 0.35 to 0.50Mrad (lMrad = 10 Kgray).
r PCT~US96/10013 A turbo-type mixer such as a homogellizer, is preferably employed for mixing lhe solulions of at least Steps 3 and 5, auld llle IlliXillg limes set forlll above are based on using a turbo-type mixer. Tllose of ordinary skill in the arl can readily select and employ other known mixers and melhods, as well as time ranges.

In a preferred embodimellt lhe present polymeric material is made by mixing lhe hydrophobic monomer in two slages to increase the solution viscosity, where in stage one the lelo-collagen complex and a mixture of rormic acid willl 2-hydroxyethyl-me~ rylale are used as a stabilizer of ultra-colloidal state solution and in stage Iwo a hydrophobic blend of at least 10 one monomer is introduced into the gel produced.

Staltdardized MetJlod for tJle Co~npounditlg of tJIe present COLL~MER

f~. Preparation of ~lcidic Collagerl Solution A lM acid solution, pre~erably lM formic acid is prepared. The quantity of acid solution l~uir~d for dissolution of llle swollen lissue is calculaled using a ratio of swollen collagen tissue: (sclera or cornea) acid solution of about 40:0.5 to 55:2, preferably about 45:1 lo about 52:1.5, most preferably about 50:1.

Tlle swollen tissue is Ihen dispellse(l in a llomogenizer for about 10 to 20 minutes, preferably about 15 minu~es at 2 to 10 RPM, preferal~ly 4-5 RPM, at room tem~e~lu~t:. The produced solution is Illen fillered througll a funnel glass filter willl a pore size of 100-150 microns, the filtrate is Ihen fil~ered Ihrougll a second funnel glass filter wilh a pore size of 5 75-100 microns. The produced llomogenic solulioll is then Iransferred inlo a container.

. Ilydrop~lobic an~ ~Iydrop~lilic SolulioJI Prepal~tion 1. The hydrophilic monomer, prererably HEMA is mixed wilh the hydropllobic 10 monomer, preferably MHr~PH in a weight ralio of about 5:1 a~id healed for one hour at 80~C
to 92~C wilh s~irrin~ (e.g., using a stirrer hot plate). The heated solu~ion is Illen filtered through 5.0 micron filter.

2. HEM~ is mixed wilh an org ulic acid (preferably formic acid), preferably in 15 a weight ratio of about 14:1. This mixture is added to the collagen solution produced (A) in a weight ratio of HEMA solu~ion:collagen solution of about 1:3, and mixed for about 20 minutes at room le.,.pe.~ture. The mixing is preferably perrormed using a homogelli e- at a rale of 6000 RPM.

CA 02223442 l997-l2-04 WO 96/40818 PCT~US96/10013 3. The HEM~ M~IBPH solulioll of 13.(1) is Illen mixed in Slllall portions willl ~ the HEMA telo-collagen solution of B.(2). Tlle mixing is preferably ~elrol.ned in a homogenizer for 10 minules at room lemperalure.

S C Production of COLLAMEI~

Glass vials are then coaled willl approximalely 7mm of paraffm wax. The solulion of 1~(3) }s then poured into the glass vials and degassed (e.g., centriruged for 15 minules to remove air). The vials are subsequenlly irradialed al 5 Kgray. (Nole: prior to irr~ ior 10 the vials can be slored in a refrigeralor, for example al 5~C to 10~C.) IY. Guid~nce for Selecting t~le Presen~ Monorners Tlle following equalion can be used lo aid in the seleclion of the ap~loplialc 15 conc~qntralion of monomer necessary lo result in Ihe presenl polymeric malerial having an index of refraction in the present desired range (1.44 to 1.48, preferably 1.45 lo 1.47, and most ~l~rer~bly 1.45 lo 1.46).

The monomer of copolymerizalion with telo-collagen comple~c is sP.I~ such that:

N = (K, ~ N~) ~ (1 - K,)Np = Nc + 0.02 K, = coefflcient of swelling N~ = refractive index of water (1.336) Np = refractive index of dry polymer N~ = refractive index of telo-collagen (about 1.45 to 1.46) ~i =n where Np = A ~ N; ~ Ci ~i=n /

N; = refractive index of i-monomer C; = concentration of i-monomer A = coeffi-~ient of increase in refractive index due to polyllleriz~tion n = number of monomers W O 96/40818 PCT~US96/10013 i = monomer number The hydrophobic and l-ydrophilic monomers must be selecled such tllat the llydlopllilic monomer is a solvent for lhe hydrophobic monomer, i.e., lhe hydropllobic monomer is soluble 5 in the hydropllilic monomer.

Tlle manner and melhod of carrying out lhe present invention may be more fully understood by lllose of skill in lhe art lo whicll tlle presenl invention pertains by reference lo lhe following examples, which examples are nol inlellded in any manner lo limit lhe scope of lhe 10 present invention or of lhe claims direcled therelo.

Examples Example ~: Compounding COLLAAIER

~. ~'reparatioll of acidic collagen solution Under an eYh~ust hood, 1 liter of dislilled waler was measured inlo a 3 liter glass beaker.
52 grams of formic acid was then added to the beaker and mixed unlil dissolved. Swollen collagen conl~inil-g lissue (frolll yig's eyes) was tllell a~l~le~l lo llle aci~ solulion in the below ralios of swollen tissue:acid solulion.

S1l~0lle~ 'ssr e ~cia' Solrllion 1. 517.00 grams 10.21 grams 2. 50.64 grams 1.00 graltls The mixlure was lhel1 slored in a rerrigeralor al a lempera~ure or5~C, and was thereafler dispersed in a homogenizer for 15 millules at 4-5 RPM at room lemperalure.
The produced solulion was lllen fillered lllrougll a funllel glass filler wilh a pore size of 100-150 microns. Tl1erearler, the fil~rale was fillere(l ll1rougll a funnel glass filter wilh a pore size of 75-100 microns. The final holnogellic solulion was thell lransrerred inLo a 250ml conlainer.
1~'. A~ PlI and ~IEll~ solrltion prepaJ~tion 1. 527.4g of I~EMA was mixecl wilh 106.2g of MHI~PI~ and healed for one hour at 80~C using a slirrer ho~ plale. The healed solulion was fillered Illrougll an Acro 50-5.0 micron filler.

W O 96/40818 PCTrUS96/10013 2. 1415.6g ofI~E M A waslllen n~ixe~ willl99.4g offomlic aci~ in a hermelic glass con~iner wilh a Tenon licl. 100g porlions or ll~eIIE M ~/aci~l solulion were added inlo 333g of lelo-collagen solulion and mixe~l for 20 millules at roon~ lemperalure. The mixing was perfonned in a holt1ogenizer at a rale of6000 I~I'M.

3. TheI-IE M A/M H~PI~solulion waslllen ad~ed in small porlions lo lhe H EM A
lelo-collagen soluLiol1. The mixil1g was performed in a llomogenizer for 10 minutes at room lempcralure.

C. Prodllction of COLLMI~ER

Glass vials were coaled wilh approximalely 7mlll of paramn wax. The resultant solulion of Slep B(3) was lllen poured inlo ll~e glass vials and cenlrifuged for 15 minules to remove air.
Tlle vials were ll1en irradialed al SKgray lo polymerize and cross-link lhe present malerial.

Example 2: Pt-epar-ation of a Uiocor rpalible Polyrneric Oplically Transparent Mate/ial In ll~is example, pig's eye sclera was used. 300g of 2-llydroxyelhyl melhacrylale was mixed willl 16g of rormic acid. 50g of lelo-collagen was fillered purified from sclera using ~lk~ hydrolysis willl 200g NaOI~ an(J 200g of Na2SO~in 2.5 Iilers of waler, and fillered througll a 100 micron filller. Tlle lelo-coll~gen was mixe(l with 2-llydroxyelllyl melhacrylale and lhe formic acid solulion conlaillill~ 2-l~ydroxyelllyl metllacrylale. 20~ of 4-~ne~ ~ryloxy-2-hydroxybellzopllenone (MHBrH) dissolved in ~EM~ was then added. This mixture was radialed wilh gamllla radialion in IllC range of 3.5-5.0 Kgray lo polymerize and cross-link ail 5 tlle components.

Hydrophol)ic monomers werc used in IhiS syslem lo reduce tlle absorplion of waler and swelling of lhe polymerized ma~erial when inlroduced inlo lhe aqueous media of tlle eye. In addilion, lhe hydropllobic monolller was chosen so lllat lhe refraclive index of the resullant 10 polymer increase~l lo be approximalely equal lo lile rerraclive index of lelo-collagen.

Example 3:

The same procedure in ~xample 2 c~ul be ulilized, excepl lllc following monomers can 15 be subsliluled:

1) elllyl-3-benzoilacrylale (ilydropllol)ic acrylic mollomer), plus 2) 2-hydlu~cyelllyl melhacrylale (1~I3M~), (llydroplli1ic acrylic .nollome,).

2(~

W O 96/40818 PCTrUS96/10013 Example 4:

The same proccdure in Example 2 can be ulilized, excepl lhe ~ollowing monomers can be subsliluled s 1) 3-allyl-4-hydroxyacelo~ ellolle (l~ydropllobic allelic monomer), plus 2) 2-llydroxyelllyl melllacrylale (III~MA), (llydropl~ilic acrylic monomer).

Example 5:

Tlle same procedure in Examl)le 2 call l~e utilize(l, except Ille following monomers can be subsliluled:

1) 2-(2'-hydroxy-3'-allyl-5'-me~llylphcnyl)-2H-benzotriazole (hydropl~obic allelic monomer), plus 2) hydroxypropyl metllacrylale, (llydropl~ilic acrylic monomer~.

E~ample 6:

Tlle same proce~lure in Exanlple 2 can bc ulilized, eXcept Ihe rollowing monollters can be subsliluled:
s 1) melllyl melllacrylate (hydropllobic acrylic monomer), plus 2) llydroxypropyl melhacrylate (lly~lropllilic acrylic mollolller).

~ artlple 7:

The same procedure in Example 2 can be ulilized, except Ille rollowing monomers can be subsliluled:

1) 2-(2'-hydroxy-3'-allyl-5'-melllyll)llellyl)-21~-bellzolriazole (hydropllobic allelic monomer), plus 2) hydro~y~lo~yl melhacrylale (hy(lropllilic acrylic monomer).

WO 96/40818 PCT~US96/10013 Example 8:

f~. Tensile Slrengl~l ï'esling of COLl~A~EI~ Malerial S The purpose of l11is ~est was lo delen11i11e llle lensi1e properlies of llle presen~ co11amer malerial. This includes ~ensi1e s~ren~,l1), Young's modulus, and percent elongalio11 at failure.
T1le da~a collecled was used lo conslruct slandards Çor inspcclio1l. The lensi1e lesl is similar lo lhe silicone lensile lesl. The saml)1e geon1clry is difrcre11l bu~ llle slress fundamenta1s remai tlle same.
1~. Malenals COLLAMEI~ samples Inslron tensile lesler (Model 1122) lS forceys log book W O 96/40818 PCTnJS96/10013 C. Proced~re 1. S~mple l'repal~tion S a. The dry malerial samples were cut inlo rings. Tlle ~ c~olls are: Oulside diameler = 10 ~ .I mm, inside diameler = B + .1 mm, llliclclless = 1.0 -~ .01 mlll. Tlle malerial was ~Jl~ed following Ille procctJures used tu manufaclure lenses. Lcnses were hydraled following MSOI' ~f 1 13 2. Tesling a. The inslron lestcr was sel up for ~ensile spe~-im~nc~ following ESOI' 202, RMX-3 Slab Pull Test, Rev I3. The fixlures were placed inlo lhe jaws an(l lhe filxlures were brought together so lhat llle lop and bollolll porlion touclled, by moving the c,v~ (l up or down. Wllen Ille fixlures were louchin~, there was apyroximalely 8 mlll belween llle lwo pms. This was llIe starlillg posilion of jaw scparalioll, so ll~e Inslroll posilion coorclinales wcre sel to zero.

b. Tlle load dial was seL lo 2 kg full scale outpul, llle c,ussllead speed lo 500 mm/mill an~l llle chart recorder to 500 mm/lllin. Tlle cllart speed ~;oll~spoll(led lo auld recorded jaw separation. The cllart bullons marked "I'I~N" and "TIME" wcre dclJI~s;~d.

c. The wel lesl sample was removed rrom ils vial and ylaced so it was almosl sLrelclled belween llle ~wo pillS. When lhe sample was in place, llle "UP" bulloll on the crosshea~ conlrol panel was imllledialely pressed. Tllis sample was Illen loaded lo failure.

~- Wllen llle sallll)lc ~ailc~, llle "sroP" l~ullon on lhe c;,o~ eA~I
conlrol panel was presse~. Tllc charl bullolls marked "PEN~ and "TIME" were lllen depressed so lllal tlley were in llle up posilion.
lhe relurn on llle crossllead conlrol panel was lhen pressed to relurn llle crosshea~l Lo slarling posilion.

WO 96/40818 PCT~US96/10013 e. Tl~e failure point in tl1e cllan was tllell marked by noting tlle load at failure (in kg) ancl jaw separalion.

f. Sleps 2a lllrougll 2e were repealed unlil all samples were all lesle~.

G Da~a C'nlel~rntiortfor Ullimate Tetlsile Slretlg~J

(1) a = ~/A

Where:

~ = Ullimale Tensile Slrellglll, I'ascals, (Pa).
F = Force required to brcak tlle lesl specimen, Newtons, (N) A = Hydrale(l cross seclional area of specimen, square melers, (m2).

ô = Swell Faclor, 1.17 w= Wi(Jlll~ mm ~ = lllic~less, mlll .

W O 96/40818 PCTnJS96/10013 civell:

= .29 kg x 9.81 m/s2 = 2.84 N
A = 2[~(w) x ~(t)]=2[(1.17 x 1.0) x (1.17 x 1.0)] = 2.74 mm2 S Conversion from mm2 lo m2: 2.74 mm2 = 2.74 x 10~ m2 A = 2.74 x l0-6 m2 I;il~(l:

Ullimale Tensile Slrengtll, Solulioll:

~ = ~/A = 2.84N12.74 x 10-6 m2 = 1038.3 kl'a lS To converl kPa lo psi, mlllliply ~y 145.04 x 103 1038.3 kPa x 145.04 x 10-3 = 150.6 psi = 1038.3 krn or a = 150.6 psi WO 96/40818 PCT~US96/10013 ~n~CI~/ntioJt for l'ercent Elongation (2) ~ = 200tL/M C~S)]

Wllere:

~ = elongatioll (specirled), percent, L = increase in jaw separalioll at specified elongalion, (mm), and MC~rS~ = meall circumrerel-ce of test specimen, mm, circum~erellce =

Givell:

L = 41.5 mm MC~TS~ rdl + 7r(1~)/2 = (~r x 10 mm ~ ~r x 8 mm)/2 = 28.27 mm Filld:

Elongation, Sollltio~

= 200[L~M C~s)] = 200~41.5 Itllll/28.27 mln] = 293.6%
= 293.C%

C~ r~1nt;onfor Yor~llg's A~o~ lus (3) E = Pl/Ae 1 0 Wllere:

E = Young's Modulus, I'ascals, (Pa) P = ~orce, Newlons, (N) l = lenglll of sample, melers (m) A = Cross Seclional Arca, square melers, (m2) e = Gross Longiludinal Deformalion, melers, (m).

WO 96/40818 PCT~US96/10013 Cive~l:

r = .29 kg x 9.81 m/s2 = 2.84 N
I = .008 m A - A = 2[~(w) x ~(1)] = 2 t(l.l7 x 1.0) x (1.17 x 1.0)~ = 2.74 mm2 Conversion from mm2 lo m2 2.74 mm2 = 2.74 x lo-6 m2 A = 2.74 x 1o6 nl2 e = .0415 m Filld:

Young's Modulus, E

SoluLion:

~ = rl/~e = (2.84 N x .OU8 m)/(.0415 m x 2.74 x 10-6 m2) = 200.2 kPa To convert kPa to psi, mulliply by 145.04 x 10-3 199.8 kPa x 145.04 x 10-3 = 29.0 psi ~ = 199.8 I~r~ or 29.0 psi CA 02223442 l997-l2-04 E, Discl~ssio~l Tlle Ins~ron was set up and calibraled accordillg lo ESOP IY202. The lesling rlxlures were brought togelher so the cenlerlines were aligned and Ihere was approximalely 8 mm belween lhe 5 posts. This was designaled ~ero and the fixlllres relurned lo this poSilioll every time afler the test. Crosshe~(l speed and lhe chart recorder speed were sel lo 500 mm/min.

The chart recorder was set al zero loa(l ancl defleclioll berore every lest. Tlle chart recorder recorded kilograms-force load and jaw separalioll. Load is used lo delermine tlle 10 ~ m~P tensile strenglll (see formula 1, Tesl Dala Seclion), lhe slress at wllicll the sample fails.
The sample was not set up to tesl elongalion using a slan~iard gage length but a formula in the ASTM D412 standard is used to calculale llle elon~ation (see formula 2, Data Section).

The performance of the specimen proved the malerial to be elaslic and willl the stress 15 increasing at a linear rale unlil failure. The linear increase can be one of two things: (1) it is possible the speci-nçns have slress risers Oll the inside di~meler. Slress risers would be caused by lhe milling process, becausefil doesn'l l~ave llle surface finish of tlle lallle-lurned ouler melçr; tllis may not allow llle malerial lo neck down during lhe plaslic deformation stage of tlle test. The majorily of the slress is concelllraled Oll tlle inlernal circulnference, which loads 20 the stress risers more than if they were on the oulside circumference; (2) Ihe material may not neck down (p1astic derormalioll) as do olher plaslic malerials such as Kaplon film. lt reacts lilce RMX-3 wilh lhe cross secliollal area gellil)g smaller as elongalion increases wllich is indicalive of Hooke's law.

Tlle present malerial showed COLLAMER good resi~l~ncP~ lo tear propagation whichwould happen at auly slress risers. Tlle cross seclional area of Ihe failed part was llat wllich was indicalive of elaslic failure.

E. COJI cl~lsioll The coml)ined data frotn lhe present COLLAMEI~ samples gave an average tensile slrength of 1084.6 kilopascals (kra) an(l an average elonga~ion of 324.9 percent (%). The tolerance ~or average lensiie slrenglll was calculaled as -~ 3 limes Ihe standard devialion giving an upper tolpr~nce of 1578 kPa (229 psi) and a lower lolerance of 591 kPa (86 psi). The tolerance for llle elongalion is calculaled in lhe san~e manner. The upper lolerance is 395 %
elongation ancl the lower tolerance is calculale~l as 255 % elongalion. See Appendix 3 for lhe calculalions. The tensile slreng~h standard is 1085 ~- 493 kPa (157 + 71 psi) and the elongation is 325% i 70. Young's modulus standard is 189 + 25 kl'a (27 + 11 psi).

W O 96/40818 PCTrUS96/10013 eferellces ASTM D412 Properlies of Rubber in Tensio ESOP 202 - RMX-3 Slab Pull Tesl, Rev I3.
Mark's S~andard Mand~ookfor Mec~anical E~lgirleers, Ninlh Edilion All references ciled are hereby incorporaled by reference. Now having fully dese~ ed lhis invention, it will be underslood by lhose of skill in lhe arl lllal lhe scope may be performed wilhin a wide and equivalenl range of con~lilions, paramelers, and lhe like, wilhout affecling lhe 10 spirit or scope of lhe invenlion or of any eml)odilnenl thereof.

Claims (18)

We Claim:

1. A biocompatible, optically transparent, polymeric material based on collagen, comprising:

one or more hydrophilic acrylic or allelic monomers, and one or more hydrophobic acrylic or allelic monomers; and telo-collagen containing telo-peptides wherein said one or more hydrophilic acrylic or allelic monomers and said one or more hydrophobic acrylic or allelic monomers, are graft-polymerized with said telo-collagen to form a biocompatible, optically transparent, polymeric material based on collagen.

2. The polymeric material of claim 1, wherein said telo-collagen has a viscosity of greater than or equal to 1000cPs.

3. The polymeric material of claim 1, wherein said one or more hydrophilic acrylic or allelic monomers are selected from the group consisting of: HEMA (acrylic); 2-hydroxyethyl methacrylate (HEMA) (acrylic); hydroxypropyl methacrylate (acrylic); 2-hydroxyethyl methacrylate (acrylic); hydroxypropyl methacrylate (acrylic); allyl alcohol (allelic); poly(ethylene glycol)n monomethacrylate (acrylic); 4-hydroxybutyl methacrylate (acrylic); allyl glucol carbonate (allelic);

said one or more hydrophobic acrylic or allelic monomers are selected from the group consisting of: 4-methacryloxy-2-hydroxybenzophenone (MHBPH) (acrylic); allyl benzene (allelic); allyl butyrate (allelic); 4-allylanisole (allelic); 3-allyl-4-hydroxyacetophenone (allelic);
2-(2'-hydroxy-3'-allyl-5'-methylphenone-2H-benzotrriazol) (allelic); N-propyl methacrylate (acrylic); ethyl-methacrylate (acrylic); methyl methacrylate (acrylic); ethyl-3-benzoil acrylate (acrylic); and n-heptyl methacrylate (acrylic); and wherein said one or more hydrophobic monomers are soluble in said one or more hydrophilic monomers.

4. The polymeric material of claim 3 wherein said hydrophilic monomer is HEMA and said hydrophobic monomer is MHBPH.

5. The polymeric material of claim 1 wherein said biocompatible optically transparent polymeric material has an index of refraction in the range of from 1.44 to 1.48.

6. The polymeric material of claim 5, wherein said index of refraction in the range of from 1.45 to 1.47.

7. The polymeric material of any one of claims 1 or 4, wherein said biocompatible, optionally transparent, polymeric material has an index of refraction in the range of from 1.45 to 1.46.

8. The polymeric material of claim 1, produced by the process comprising:

dissolving an acid-telo-collagen solution in one or more hydrophilic monomers to form a collagen/hydrophilic solution;

dissolving one or more hydrophobic monomers in one or more hydrophilic monomers to form a hydrophobic/hydrophilic solution;

combining said collagen/hydrophilic and said hydrophobic/hydrophilic solution to form a resultant solution; and graft-polymerizing said resultant solution to form the present biocompatible, optically transparent, polymeric material based on collagen.

9. A method for producing a biocompatible, optically transparent, polymeric material, comprising:

dissolving an acid-telo-collagen solution in one or more hydrophilic monomers to form a collagen/hydrophilic solution;

dissolving one or more hydrophobic monomers in one or more hydrophilic monomers to form a hydrophobic/hydrophilic solution;

combining said collagen/hydrophilic and said hydrophobic/hydrophilic solution to form a resultant solution; and graft-polymerizing said resultant solution to form the present biocompatible, optically transparent, polymeric material based on collagen.

10. The method of claim 9, wherein said step of graft-polymerizing comprises irradiating said resultant solution.

11. A deformable lens comprising:

the biocompatible, optically transparent, polymeric material based on collagen of claim 1.

12. The deformable lens of claim 11, wherein said deformable lens is a contact lens.

13. The deformable lens of claim 11, wherein said deformable lens is a sort intraocular lens.

14. The deformable lens of claim 11, wherein said deformable lens is a refractive intraocular lens.

15. A method for correcting aphekia, myopia or hypermetropia in a patient suffering therefrom, comprising:

implanting in the eye of said patient, the intraocular lens of any one of claims 13 or 14.

16. The polymeric material of claim 1, wherein said polymeric material has a tensile strength of from about 591 kPa to about 1578 kPa.

17. The deformable lens of claim 11, wherein said deformable lens has a tensile strength of from about 591 kPa to about 1578 kPa.

18. A deformable lens comprising:

the biocompatible, optically transparent polymeric material of claim 4.